Enteric coated dosage forms are well-known among products in the pharmaceutical industry.
In enteric coated products, the dosage form remains intact in the stomach, but dissolves and releases the active ingredient(s) in the upper intestine. The reasons for applying enteric coatings to oral solid formulations are (a) to protect the drug from the destructive action of the enzymes or low pH environment of the stomach e.g., erythromycin (b) to prevent nausea or bleeding associated with the irritation of the gastric mucosa as in the case of aspirin or potassium chloride and/or (c) to deliver the drug in an undiluted form in the intestine e.g., intestinal antibacterial agents or vermifuges. Based on these criteria, enteric coated products may be regarded as a type of delayed action dosage form. They differ from sustained release products in that with sustained release products, the drug release is extended over a period of time to maintain therapeutic blood levels and to decrease the incidence of side effects caused by a rapid release; whereas, with enteric coatings, the primary objective is to confine the release of the drug to a predetermined region of the gastrointestinal tract. Some of the enteric coated preparations currently sold in the United States are shown in the following Table 1.
TABLE I ______________________________________ Enteric Coating Dosage Product Drug Form Manufacturer ______________________________________ Cotazyme-S .TM. Pancrealipase Pellets in a Organon Capsule Depakote .RTM. Divalproex Tablet Abbott Sodium Laboratories Dulcolax .RTM. Bisacodyl Tablet Boehringer Ingelheim Easprin .RTM. Aspirin Tablet Parke-Davis Ecotrin .RTM. Aspirin Tablet Menley & James Eryc .RTM. Erythromycin Pellets in a Parke-Davis Capsule Ery-Tab .RTM. Erythromycin Tablet Abbott Laboratories PCE .TM. Erythromycin Polymer Coated Abbott Particles in a Laboratories Tablet ______________________________________
In addition to the advantages cited above, enteric coated dosage forms can fulfill a distinct need that arises frequently in drug discovery programs. During early stages of drug development i.e. in preclinical and early Phase I trials, some new chemical entities used in the health care industry present a challenge in testing for efficacy due to instability in gastric fluids or because of irritation in the gastrointestinal tract. In these situations, enteric coating of the encapsulated drug formulations would enable an investigator to determine the efficacy of the experimental drug free from the complications of gastric instability or irritation. The very limited amount of bulk material available during the early developmental stage and the fact that the chemical synthetic process has not been standardized preclude the manufacture of an optimized enteric coated pellet or tablet formulation for human or animal testing. Under these conditions, the benefits resulting from the availability of enteric coated capsule products are obvious, since the coating process will be independent of the capsule contents. Thus, the oral pharmacological and/or therapeutic efficacy of the new chemical entities can be ascertained without resorting to extensive formulation development studies which are costly, time-consuming, and, in many instances, infeasible at this point in the development of the new chemical entities.
While the currently marketed enteric coated dosage forms are either compressed tablets or pellets filled into capsules, a number of studies involving coated hard gelatin capsules have been reported in the literature. See Baum, J., "Enteric coated aspirin today", J. Rhumatology, 12, 829 (1985) and Pollet, S., White, R. H., Jang, H., Yim, C. W., and Feigal, D., "Aspirin dosing using 15 grain enteric coated tablets", J. Rhumatology, 12, 337 (1985). These involve the use of formalin-treated gelatin and shellac. Both of these natural materials suffer from the disadvantage of uncontrolled polymerization, during processing or storage, resulting in failure to release the drug in the small intestine.
An enteric product may fail to deliver the required performance due to either a lack of gastric resistance or through failure to release the active ingredient(s) in the intestine. In addition, erratic absorption was reported with some enteric coated products coated with shellac, although more recently marketed products were shown to provide reliable absorption. See Madan, P. L., "Sustained release drug delivery systems, Part IV--Oral products", Pharm. Mfg., 2, 41 (1985) and Pondell, R. E., "From solvents to aqueous coatings," Drug Develop. Ind. Pharm., 10, 191 (1984).
The chemical structure of the commonly used polymers for enteric coating purposes is shown as follows. ##STR1## These contain ionizable carboxyl groups as an integral part of the molecule. The action of the enteric coating stems from a difference in the pH environments of the gastric and intestinal fluids. Within the low pH environment of gastric fluid, these polymers exist in their undissociated state and are insoluble. They ionize and become soluble as the pH rises to 5.0 and above in the intestinal fluids permitting dissolution and absorption of the active ingredient.
Traditionally, enteric polymers are applied onto substrates as solutions in organic solvents. The solvents commonly employed as vehicles are methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, and combinations thereof. The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution. However, during the last decade, the use of organic solvents in pharmaceutical film-coating operations has come into disrepute because of high cost, flammability, toxlcity of the residual solvent in the dosage form. These disadvantages spurred the exploration of suitable alternatives that ultimately lead to the commercial manufacture and availability of aqueous systems. Currently, three aqueous enteric polymer coatings are available for commercial use in the United States. These are Eudragit.RTM. L30D (methacrylic acid-methacrylic acid ester copolymer marketed by Rohm-Haas GmBH, West Germany), Aquateric.RTM. Cellulose Acetate Phthalate-containing product marketed by FMC Corporation, Philadelphia, Pa.) and Coateric.TM. (a polyvinyl acetate phthalate-based product marketed by Colorcon, Inc., West Point, Pa.). Unlike organic solutions, these aqueous-based systems can be prepared at high concentrations without encountering high viscosity.
It should be noted that the use of aqueous enteric coatings also involves certain liabilities. As a result of the low volatility of water, higher costs are associated with their use while drying the coats. Also, the presence of residual moisture may have a deleterious effect on the chemical and physical stability of the product as well as possibly providing a medium for microbial growth in some instances.
Previously the feasibility of preparing enteric coated capsules have been evaluated using the three commercially available aqueous latex polymeric dispersions (Eudragit.RTM. L30D, Aquateric.RTM., and Coateric.TM.) and procainamide hydrochloride capsules as the model substrate. The effective range of coating levels was not established for the acrylic resins and their derivatives until the present inventor showed such levels. See Murthy, K. S., et al, "Comparative Evaluation of Aqueous Enteric Polymers in Capsule Coatings", Pharm. Tech., 10, 36 (1986). However, stability of the enteric coating comprising the acetates and their derivatives by high levels of coating proved to be less than desirable.
The present invention improves the stability of the capsules through the application of higher levels of coatings or by the application of higher levels of coatings in combination with the use of a protective coating. The stability characteristics of capsules coated with the aqueous dispersions according to the present invention are unexpectedly improved compared to similar coatings achieved through the use of organic solvents as well as known use of aqueous films for enteric coating. Coated capsules were stored under accelerated conditions, 37.degree. C./80% RH and 45.degree. C., for six to eight weeks. SEM examination and TMA analysis of coatings show the unexpectedly improved nature and characteristics of the films of the present invention.
Although a coating process which improves thermic and dimensional stability of capsules is taught in Belgian Patent 881,462 such a teaching does not make obvious the present invention use of a heavier enteric coating or a heavier enteric coating in combination with a further coating of an enteric dosage form. Also the present invention can be distinguished from the use of a water-soluble overcoat for alleviating tackiness and slow curing of sustained release dosage forms as found in the patents or applications in U.S. Pat. No. 4,600,645; W083/00284; U.S. Pat. No. 4,176,175; and British 2043442. That is, the improvement of the overcoat and the sustained release formulation are different from the present inventions. Similarly, the present invention is readily distinguished from the treble layers required in U.S. Pat. No. 4,001,390 because in this disclosure the layers are not for an enteric dosage form as now set out in the present invention.